Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial

医学 改良兰金量表 随机对照试验 缺血性中风 冲程(发动机) 纤溶剂 临床试验 外科 内科学 组织纤溶酶原激活剂 缺血 缺血性中风 替代医学 安慰剂 病理 工程类 机械工程
作者
Michael D. Hill,Mayank Goyal,Bijoy K. Menon,Raul G Nogueira,Ryan McTaggart,Andrew M. Demchuk,Alexandre Y. Poppe,Brian Buck,Thalia S. Field,Dar Dowlatshahi,Brian van Adel,Richard H. Swartz,Ruchir Shah,Eric Sauvageau,Charlotte Zerna,Johanna M. Ospel,Manish Joshi,Mohammed Almekhlafi,Karla J. Ryckborst,Mark Lowerison,Kathy Heard,David Garman,Diogo C Haussen,Shawna M Cutting,Shelagh B. Coutts,Daniel Roy,Jeremy Rempel,Axel Rohr,Daniela Iancu,Demetrios J. Sahlas,Amy Yu,Thomas Devlin,Ricardó A. Hanel,Volker Puetz,Frank L. Silver,Bruce Campbell,René Chapot,Jeanne Teitelbaum,Jennifer Mandzia,Timothy Kleinig,David Turkel‐Parrella,Donald Heck,Michael Kelly,Aditya Bharatha,Oh Young Bang,Ashutosh P. Jadhav,Rishi Gupta,Donald Frei,Jason W Tarpley,Cameron McDougall,Staffan Holmin,Joung‐Ho Rha,Ajit S Puri,Marie‐Christine Camden,Götz Thomalla,Hana Choe,Stephen Phillips,Joseph Schindler,John Thornton,Simon Nagel,Ji Hoe Heo,Sung‐Il Sohn,Marios‐Nikos Psychogios,Ronald Budzik,Sidney Starkman,Coleman Martin,Paul Burns,Seán Murphy,George Α. Lopez,Joey English,Michael Tymianski,Andrew M. Demchuk,Philip A. Barber,Eric E. Smith,Simerpreet Bal,Suresh Subramaniam,Steven Peters,Phillippe Couillard,Gary Klein,Peter K. Stys,Bijoy K. Menon,Shelagh B. Coutts,Mohammed Almekhlafi,Michael D. Hill,Mayank Goyal,John Wong,Alim P. Mitha,Muneer Eesa,William Morrish,Saad Alqatani,Nima Kashani,Manish Joshi,Charlotte Zerna,Johanna M. Ospel,Prasanna Venkatesan,Erika Teleg,Amith Sitaram,Brett Graham,Stephen van Gaal,Aimen Moussaddy,Debabrata Chakraborty,Nicholas Maraj,Andrew Loockey,Shuo Chen,Ravinder Singh,Abdulaziz S. Al Sultan,R.M. Asuncion,Dominic Tse,Darshan Doshi,Ondřej Volný,Piyush Ojha,Ankur Wadhwa,Martha Marko,Nishita Singh,Sanchea Wasyliw,Karla J. Ryckborst,Carol Kenney,Supriya Save,Anitha Jambula,Nancy Newcommon,Gavin Hull,Darcy Blackstock,Sharon Kiszczak,L Zimmel,Michelle Wright,Cari Jahraus,Linda Andersen,Shelly Bohn,Joseph Paul,Oiao Zhang,Craig Doram,Mark Lowerison,Andrea Hanley,Lori Campbell,Ashley Ure,F W Taylor,Dominic Hul,Samuel Wiebe,Marina Saluzzi,Nicole Blenkin,Richard Frayne,Brian Buck,Kenneth Butcher,Ashfaq Shuaib,Tom Jeerakathil,Glen C. Jickling,Derek Emery,Jeremy Rempel,Richard Owen,Robert Ashforth,Tom Yeo,Trevor Kotylak,Cian O’Kelly,Michael Chow,Muzaffer Siddiqui,Maher Saqqur,Atlantic D’Souza,Mar Lloret,Asif Butt,Ali Zohair Nomani,Hayrapet Kalashyan,Sibi Thirunavukkarasu,Juline Jabs,Paige Fairall,Lori Piquette,Stephen Phillips,A. Laine Green,Gordon Gubitz,Jens Heidenreich,Thien Huynh,Jai Shankar,William J. Maloney,Robert Vandorpe,Matthias H. Schmidt,Gwynedd E. Pickett,Adrienne Weeks,J Jarrett,Debbie MacDonald,Joanna Arsenault,Ruth Kinnear,Jennifer Mandzia,Michael Mayich,Melfort Boulton,María Bres Bullrich,Sebastián Fridman,Ruba Kiwan,Donald Lee,Stephen Lownie,Alexander V. Khaw,Sachin Pandey,Manas Sharma,Luciano A. Sposato,Kevin Wade,Beth Beauchamp,Lindsay Lambourn,Belinda Amato-Marziali,Alexandre Y. Poppe,Daniel Roy,Nicole Daneault,Yan Deschaintre,Laura Gioia,Grégory Jacquin,Céline Odier,Christian Stapf,Daniela Iancu,Jean Raymond,Alain Weill,Marlène Lapierre,Nadia Jadil,Judlène Jolteus,Jeanne Teitelbaum,Mark Angle,Mathew Hannouche,Mohamed Badawy,Justin Létourneau,Maria Cortes,Grant Linnell,Donateela Tampieri,Lucy Vieira,Aimen Moussaddy,Catherine Legault,Liam Durcan,Angela Moore,Erin L. Cole,Claire Magnussen,Kristiana Salmon,Salma Khalil,Isabelle Desloges,Lindsay Waxman,Wynne Abdon,Sonia Lai,Dar Dowlatshahi,Daniela Iancu,Michel Shamy,Grant Stotts,Dylan Blacquière,Howard Lesiuk,Aiman Quateen,Brian Drake,Brian Dewar,Zeinab Daham,Michael Kelly,Gary Hunter,Lissa Peeling,Brett Graham,Ruth Whelan,Aaron Garner,Lilian Urroz,Sharleen Maley,Frank L. Silver,Leanne K. Casaubon,Aleksandra Pikula,Martín del Campo,Joanna D. Schaafsma,Cheryl Jaigobin,Timo Krings,Vítor Mendes Pereira,Ronit Agid,Richard Farb,Libby Kalman,Anne Cayley,Janice E. Williams,Tim Stewart,Karen Misquitta,Aditya Bharatha,Daniel Selchen,Thomas R. Marotta,Dipanka Sarma,Walter Montanera,Juluan Spears,Gustavo Saposnik,Pawel Kostyrko,Yangmei Li,Carmen Parra-Farina,Jose Danilo Bengzon Diestro,Marie‐Christine Camden,Steve Verreault,Ariane Mackey,Marie‐Ève Audet,Geneviève Milot,Pascale Lavoie,Jean‐Luc Gariépy,Karine Collard,Annette Haché,Brian van Adel,Demetrios J. Sahlas,Ahmed M. Alshanbari,Josephine Baldwin,Luciana Catanese,Bing Chen,Danielle de Sá Boasquevisque,Aviraj Deshmukh,Jordan Knapman,Shana Lamers,Ramiro Larrazabal,Susan Macmillan,Lauren Mai,Alicia Mattia,Sumiti Nayar,Kuan H. Ng,Wieslaw Oczkowski,Kanjana Perera,Mays Shawawrah,Ashkan Shoamanesh,Gita Sobhi,Nabeel Muzaffar Syed,Noran Taher,Cheyanne Vandervelde,D Pharm,Thalia S. Field,Stephen van Gaal,Philip Teal,Oscar Benavente,Laura Wilson,Sharanpal Mann,Samuel Yip,Colleen Murphy,Manraj K. S. Heran,Axel Rohr,Fabio Settecase,Gary Redekop,Charles S. Haw,Genoveva Maclean,Karina Murray,Rosalin Chiu,Alana M. Flexman,Eilidh Strecha,Yolanda Gayton,Judy Yip,Richard H. Swartz,Mark I. Boulos,David J. Gladstone,Amy Yu,Julia Hopyan,Houman Khosravani,Herbert Manosalva Alzate,Alisia Southwell,Maneesha Kamra,Kaitlyn Lopes,Arunima Kapoor,Leodante da Costa,Victor X. D. Yang,Erin Dyer,Ruchir Shah,Brenda Knowles,Jennifer Nichols,Jennifer Patterson,Krista A. Cope,Lee Dickerson,Katrina Barton,Kimberly Gray,Ticey N. Massengale,Melanie M. Miller,Cindy Simpson,Sabrina Walker,Chlin R. Tennyson-Yemm,Thomas Devlin,Donald Frei,Richard Bellon,Benjamin Atchie,Ian Kaminsky,Duandelyn C. Wilson,Nicolle L. Schraeder,Eric Arias,Lisa M. Kodis,Mark E. Talley,Alex A. Edinger,Tiffany Talley,Ita P. Dempsey,Laurie Williams,Scott A. Williams,Sonny Kupniewski,Brad K. Fasbinder,Joanna M. Snead,Hana Choe,Larami Mackenzie,D. Weisman,Osman Kozak,Qaisar Shah,Dan Gzesh,Kandan Kulandaivel,John Khoury,Brad Klein,Patricia Bussinger,Lisa Griffin,Ashley L. DePalmo,Cynthia Oliva,Ashutosh P. Jadhav,Tudor Jovin,Cynthia L. Kenmuir,Brian T. Jankowitz,Bradley A. Gross,Marcelo Rocha,Matthew Starr,Merritt Brown,Christine Hawkes,Kavit Shah,Danoushka Tememe,Gregory Walker,Pratit Patel,Bradley Klein,Habibullah Ziayee,Kaustubh Limaye,Lisa Baxendell,Vicki Gilchrist,Patricia Feineigle,Kelsea Toseki Haibach,Cathy Van Every,Shashyat Desai,Maryam Zulfiqar,Linda Gibson‐Young,Sean P. Barrett,David Turkel‐Parrella,Karthikeyan Arcot,Steven DiCrescento,Jeffrey Farkas,Gregory Filipowski,Jennifer Frontera,Danielle Joset,Jeremy Liff,Erica Scher,Cameron McDougall,Cheryl E. Kelly,Akshal Patel,Stephen J. Monteith,Sidney Starkman,Kunakorn Atchaneeyasakul,Adrian M Burgos,Janice Anne Y. Chua,Nathan Gaines,Ileana Grunberg,Judy Guzy,Zuolu Liu,Neil D. Maluste,Lucas Ramírez,Laxmi Kant Sharma,Donald Heck,M Brown,Colin T. McDonald,Mateo Calderon,Mitch Hargis,Christina Roels,Prabhu D. Emmady,Talat Alvi,Ryan McTaggart,Mahesh Jayaraman,Shawna Cutting,Wendy Smith,Susan M. Foley,G Paolucci,Richard Has,Katie Quinn,Lindsey Fuller,Rebecca E. Brierley,Christina C. Watkins,Nicole C. Demir,George Α. Lopez,Alejandro Vargas,Nicholas Osteraas,Becky Holtz,Eric Sauvageau,Ricardó A. Hanel,Amin Aghaebrahim,Mohamad Chmayssani,Neeraj S. Naval,Jason S. Day,Scott Dellorso,Benjamin J. Ludwig,Derek J. Schemmel,Nancy Ebreo,Karen Bell,Lanai Lewis,Marjorie Delucia,Raul G Nogueira,Diogo C Haussen,Michael Frankel,Nirav Bhatt,Nicolas Bianchi,Aaron Anderson,Samir Belagaje,Bernardo Liberato,Srikant Rangaraju,Alhamza R Al‐Bayati,Jonathan A Grossberg,Leah Craft,Kiva Schindler,Erin Schaad,Meagan Schultz,Lorretta Southerly,Shannon Doppelheuer,Jacquelyn Charlton,Jason Faggard,Zuzana Barbret,Ethan DukSoo Han,Robin Walters,Jaydevsinh Dolia,Sleiman El-Jamal,Brendan Eby,Yasir Saleem,Harrison Pearl,Kishan Patel,Haseeb Rahman,Reema Butt,Stephen English,Ajit S Puri,M Howk,Jasmeet Singh,Francesco Massari,Katyucia DeMacedo Rodrigues,Anna Luisa Kühn,Joey English,Nobl Barazangi,Nick Telischak,Warren Kim,Josh Ross,Nata DeVole,Jessica Redford,Milena Ferreira,Katie Ponting,Helen Shen,Ann Bedenk,Susila Patel,Julia Fernandess,Michael Ke,Ilanit Spokoyny,Billy Gao,David Tong,Xiaomeng Chen,Christine Wong,Jessica Choe,Coleman Martin,Debbie Summers,Christine Boutwell,Karin Olds,Suzanne Crandall,John Eatman,Naveed Akhtar,W Holloway,J Halpin,Brett Donegan,Joseph Schindler,David Y. Hwang,Emily J. Gilmore,Nils Petersen,Kevin N. Sheth,Stacy Brown,Rachel Beekman,Benjamin P. George,Firas Kaddouh,Guido J. Falcone,Charles Wira,Charles Matouk,Caitlin Loomis,Hardik Amin,Christoph Stretz,Reshma Narula,Adam Jasne,Lauren Sansing,Tijil Agarwal,Sara Jasak,Dominique Fontaine,Zachary A. King,Lindsey Kuohn,Hailey Orgass,Megan Leary,Joan Nye,Kelsey Halbert,Karin Nyström,Kaile Neuschatz,Dawn M. Petrucci,Anna Coppola,Jason W Tarpley,Treasure A. Joyce,Sam Hou,Mark S. Umekubo,Catrice M. Nakamura,Renee Ovando,Diana Zúñiga,Yih Lin Nien,Fernando Mayor Basto,Allison E. Arch,Laura W. de Jong,William A. Conrad,Tara C. Abbott,Jay Yao,Scott D. Caganap,John E. Jordan,George P. Teitelbaum,Robert Darflinger,Rishi Gupta,Marianne Bain,Ronald Budzik,Jennifer H. Czerniak,Katherine M. Groezinger,William J. Hicks,Omran Kaskar,Brian Katz,Aaron Loochtan,Peter Pema,Vivek Rai,Nirav Vora,Amanda Brown,Diane Goodman,Barb Danenbergs,Monica Gossett,Oh Young Bang,Jong‐Won Chung,Pyoung Jeon,Keon Ha Kim,Yun Jeong Lim,Ji Hoe Heo,Hyo Suk Nam,Young Dae Kim,Hyungjong Park,In Gun Hwang,Woo-Seok Ha,Jin Kyo Choi,Kyungsun Jeong,Joung‐Ho Rha,Hee-Kwon Park,Cindy W. Yoon,Bokyung Kim,Sung‐Il Sohn,Chang-Hyun Kim,Joonsang Yoo,Jeong‐Ho Hong,Hyungjong Park,Sohyeon Kim,Moonkyung Choi,Hyoeun Bae,Jun Seok Lee,Jae‐Joon Lee,Go-Eun Jun,Sujeong Jeon,Bruce Campbell,Peter Mitchell,Nawaf Yassi,Stephen M. Davis,Geoffrey A. Donnan,Mark Parsons,Bernard Yan,Richard Dowling,Steven Bush,Teddy Y. Wu,Darshan Shah,Henry Zhao,Patrick Salvaris,Fana Alemseged,Felix Ng,Cameron Williams,Anna Balabanski,Angela Dos Santos,Jo-Lyn Ng,Amy McDonald,David M. Jackson,Jessica Tsoleridis,Lauren Pesavento,Timothy Kleinig,Roy Drew Nurs,Thalia S. Field,Rebecca Scroop,Lavenia Cagi,Jackson Harvey,Michael F. Waters,John Thornton,Robert T. Brennan,Alan O’Hare,Sarah Power,David Williams,Karl Boyle,Barry Moynihan,Ann-Marie Liddy,Margaret Large,Ailbhe Cullen,Roisin Walsh,Emma Martin,Julie Lynch,Sinéad McElroy,Seán Murphy,Sarah Coveney,Caroline Deegan,Gillian Horgan,Peter J. Kelly,Aoife Laffan,Yudy Llamas-Osorio,Catherine Lynch,Peter Mac Mahon,Michael Marnane,John McCabe,Paul Burns,Suzanne Tauro,Sarah Cuddy,Ian Rennie,Graham Smyth,Peter Flynn,Ivan Wiggam,Enda Kerr,Patricia L. Gordon,Patricia Fearon,Geralt Roberts,Cathy Patterson,Karen E. Adams,Brian Wells,Margaret McFarland,Staffan Holmin,Tiago Moreira,Christina Sjöstrand,Michael V. Mazya,Håkan Almqvist,Nils Wahlgren,Anna Steinberg,Charith Cooray,Einar E. Eriksson,M. Thorén,Boris Keselman,Niaz Ahmed,Åke Holmberg,Maria Axelsson,Annika Berglund,Götz Thomalla,Amir Golsari,Julia Hoppe,Milani Deb‐Chatterji,Bastian Cheng,E Barrow,Eckhard Schlemm,Iris Lettow,Märit Jensen,Dagmar Otto,Kirsten Jaramillo,Hannes Appelbohm,Jens Fiehler,Maxim Bester,Michael Schönfeld,Caspar Brekenfeld,Brigitte Holst,Ginette Wortmann,Friederike Koch,Volker Puetz,Johannes Gerber,Andrij Abramyuk,Daniel Kaiser,Simon Winzer,Alexandra Prakapenia,Lars‐Peder Pallesen,Timo Siepmann,Kristian Barlinn,Kathrin Haase,Angela Sauer,Marios‐Nikos Psychogios,Jan Liman,Alex Brehm,Volker Maus,Nicole Hollstein,Annika Reinke,Gustav Neitz,Marlena Schnieder,Margret Schwarz,Allam Ibrahim,Julia Müller,Stefanie Meister,Berit Bäumle,René Chapot,Sara Pilgram‐Pastor,Marta Wallocha,Michael C. Stauder,Ekin Celik,Paul Stracke,Nicole Müller,Ralph Weber,Roland Velktamp,Simon Nagel,Peter A. Ringleb,Miriam Heyse,Hemasse Amiri,Sibu Mundiyanapurath,Min Chen,Elisabeth Bevrle,Perdita Beck,Markus Möhlenbruch,Michael Tymianski,Alphonse R.J. Potvin,Cameron Harris,Chong Wang,Corey Adams,Diana Mayor,D. Melissa Garman,Davis Chau,Jane Wu,Janet Lunn,Kathy Heard,Liat Bermanis,Lucy Teyes,Marc Constant,Maria Galsim,Michael Helbin,Michelle Leroux,Nicole Felix,Nilima Bendre,Sandra Cuthbert,Steve Brokx,Yichuan Zhang,Trudy Lingham,Yatika Kohli,Michael W. Salter,Joseph Liebeschuetz,Frieder Hofmann,John Constant,Tom Soeder,Kara Snoke,Monica Bologa,Kimberly Stahl,Maria A Graziewicz
出处
期刊:The Lancet [Elsevier]
卷期号:395 (10227): 878-887 被引量:463
标识
DOI:10.1016/s0140-6736(20)30258-0
摘要

Background Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. Methods For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0–2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0–1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. Findings Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0–2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96–1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. Interpretation Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. Funding Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
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